The sympathetic nervous system is critically involved in the pathogenesis of heart failure (HF). It is now currently well recognized from clinical studies that inhibiting sympathetic activity is salutary in HF. Whereas this approach is now routine clinically there are some limitations to the usefulness of this therapeutic approach of inhibiting sympathetic activity at the level of -adrenergic receptors (-AR) in some patients with HF. The overall goal of this project is to explore the role of inhibiting -AR at the level of adenylyl cyclase (AC) and to study a potentially new therapeutic approach for HF, i.e., inhibition of type 5 adenylyl cyclase (AC5). Our overall hypothesis is that AC5 is a key enzyme mediating cardiomyopathy in response to cardiac overload and secondarily to increased -AR signaling or to cardiomyopathy induced by chronically enhanced -AR signaling in mice with overexpressed 1-AR or 2-AR and that inhibition of AC5 rescues the cardiomyopathy in these transgenic (Tg) mice. One might suppose that reducing AC activity will, by itself, be responsible for rescuing -AR cardiomyopathy. However, the main source of AC activity in the heart is AC6, and, since we have demonstrated that AC5 KO only exhibit a 25-30% reduction in AC activity, the rescue of 2-AR Tg cardiomyopathy must involve a complex interaction of mechanisms, not simply due to the modest decrease in AC activity. The goal of this project is to determine the mechanisms underlying rescue of cardiomyopathy by inhibition of AC5, which will support the clinical use of this molecule as a novel treatment for HF. There are three major hypotheses: Hypothesis A: Inhibition of AC5 protects against cell death and rescues the cardiomyopathy induced by overexpressed 1-AR or 2-AR. Hypothesis B: The rescue of the 1-AR Tg or 2-AR Tg cardiomyopathies by inhibition of AC5 permits enhanced exercise performance which is due to (1) improved cardiac output and stroke volume, (2) improved coronary reserve, and (3) enhanced nitric oxide (NO) signaling. Hypothesis C: Resistance to oxidative stress is an important mechanism in the protection against cell death and rescue of cardiomyopathy in 1-AR Tg x AC5 knockout (KO) or 2-AR Tg x AC5 KO bigenic mice. The implications for Public Health are self-evident, considering that heart disease and HF are the disease processes which have the greatest impact on Public Health in the US, in terms of finances and task-force, and using similar logic, finding new therapies will be crucial to minimize the impact of these disease states on Public Health.